Development of a Novel B-Cell Lymphoma 6 (BCL6) PROTAC To Provide Insight into Small Molecule Targeting of BCL6

McCoull, William; Cheung, Tony; Anderson, Erica; Barton, Peter; Burgess, Jonathan; Byth, Kate; Cao, Qing; Castaldi, M. Paola; Chen, Huawei; Chiarparin, Elisabetta; Carbajo, Rodrigo J.; Code, Erin; Cowan, Suzanna; Davey, Paul R.; Ferguson, Andrew D.; Fillery, Shaun; Fuller, Nathan O.; Gao, Ning; Hargreaves, David; Howard, Martin R.; Hu, Jun; Kawatkar, Aarti; Kemmitt, Paul D.; Leo, Elisabetta; Molina, Daniel M.; O’Connell, Nichole; Petteruti, Philip; Rasmusson, Timothy; Raubo, Piotr; Rawlins, Philip B.; Ricchiuto, Piero; Robb, Graeme R.; Schenone, Monica; Waring, Michael J.; Zinda, Michael; Fawell, Stephen; Wilson, David M.

doi:10.1021/acschembio.8b00698

Title: Development of a Novel B-Cell Lymphoma 6 (BCL6) PROTAC To Provide Insight into Small Molecule Targeting of BCL6

Journal Article · Wed Oct 17 00:00:00 UTC 2018 · ACS Chemical Biology

DOI: https://doi.org/10.1021/acschembio.8b00698 · OSTI ID:1544823

^[1]; Cheung, Tony ^[2]; Anderson, Erica ^[2]; Barton, Peter ^[1]; Burgess, Jonathan ^[1]; Byth, Kate ^[2]; Cao, Qing ^[2]; Castaldi, M. Paola ^[2]; Chen, Huawei ^[2]; Chiarparin, Elisabetta ^[1]; Carbajo, Rodrigo J. ^[3]; Code, Erin ^[2]; Cowan, Suzanna ^[1]; Davey, Paul R. ^[1];

^[2]; Fillery, Shaun ^[1]; Fuller, Nathan O. ^[2]; Gao, Ning ^[2]; Hargreaves, David ^[1]; Howard, Martin R. ^[1] more »

AstraZeneca, Cambridge (United Kingdom)
AstraZeneca, Waltham, MA (United States)
AstraZeneca, Cambridge (United Kingdom).
Pelago Bioscience AB, Solna (Sweden)
Broad Inst. of Harvard and MIT, Cambridge, MA (United States)

B-cell lymphoma 6 (BCL6) inhibition is a promising mechanism for treating hematological cancers but high quality chemical probes are necessary to evaluate its therapeutic potential. In this paper we report potent BCL6 inhibitors that demonstrate cellular target engagement and exhibit exquisite selectivity for BCL6 based on mass spectrometry analyses following chemical proteomic pull down. Importantly, a proteolysis-targeting chimera (PROTAC) was also developed and shown to significantly degrade BCL6 in a number of diffuse large B-cell lymphoma (DLBCL) cell lines, but neither BCL6 inhibition nor degradation selectively induced marked phenotypic response. To investigate, we monitored PROTAC directed BCL6 degradation in DLBCL OCI-Ly1 cells by immunofluorescence and discovered a residual BCL6 population. Analysis of subcellular fractions also showed incomplete BCL6 degradation in all fractions despite having measurable PROTAC concentrations, together providing a rationale for the weak antiproliferative response seen with both BCL6 inhibitor and degrader. In summary, we have developed potent and selective BCL6 inhibitors and a BCL6 PROTAC that effectively degraded BCL6, but both modalities failed to induce a significant phenotypic response in DLBCL despite achieving cellular concentrations.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE

OSTI ID:: 1544823

Journal Information:: ACS Chemical Biology, Journal Name: ACS Chemical Biology Journal Issue: 11 Vol. 13; ISSN 1554-8929

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Degradation of proteins by PROTACs and other strategies Wang, Yang; Jiang, Xueyang; Feng, Feng Acta Pharmaceutica Sinica B, Vol. 10, Issue 2 https://doi.org/10.1016/j.apsb.2019.08.001	journal	February 2020
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Title: Development of a Novel B-Cell Lymphoma 6 (BCL6) PROTAC To Provide Insight into Small Molecule Targeting of BCL6

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